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Vol. 295, Issue 2, 438-446, November 2000

Multiple Central Nervous System Targets for Eliciting Beneficial Effects on Memory and Cognition1

Jerry J. Buccafusco and Alvin V. Terry, Jr.

Alzheimer's Research Center, Department of Pharmacology and Toxicology (J.J.B., A.V.T.), University of Georgia, College of Pharmacy (A.V.T.), Medical College of Georgia, Augusta, Georgia; and Veterans Affairs Medical Center, Augusta, Georgia (J.J.B.)

The development of drugs for the treatment of disorders of cognition has benefited from a more precise knowledge of the loss of specific neural pathways associated with certain neurodegenerative diseases such as Alzheimer's disease (AD). The loss of basal forebrain cholinergic neurons in AD has engendered the development of new compounds that target various aspects of the cholinergic system. However, limitations in the effectiveness of the most common of these, the anticholinesterases, have fueled the race to provide more efficacious compounds. In an attempt to avoid side effects and improve efficacy, other neuronal targets have been considered, including receptors for norepinephrine, dopamine, serotonin, excitatory amino acids, neural peptides, and others. Our laboratory has had the opportunity to study the memory-enhancing potential of many of the compounds developed expressly for these neuronal targets in macaques. Upon reviewing 21 such studies it was evident that: 1) To varying degrees, pharmacological manipulation of each target yielded improved task performance. 2) Combining pharmacological targets could lead to additive or synergistic effects on task performance. 3) Mature adult and aged monkeys provided equivalent estimates of drug effectiveness. 4) There appeared to be no limiting level of task improvement for compounds tested in aged and younger monkeys. 5) Certain of these agents also exhibited potential disease-modifying actions. Thus, certain memory-enhancing agents may prove more useful when implemented early in the course of a disease such as AD, and they also may enjoy a wide application for the treatment of the memory decline associated with normal aging.

1 This work was supported in part by Abbott Laboratories, Hoechst Marion Roussel, Roche Bioscience, SIBIA Neurosciences, Inc., Wyeth-Ayerst Research, the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, and the Alzheimer's Association.

0022-3565/00/2952-0438$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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